Programming brain cells to turn their own light on and off, like a firefly

A new promising technology could offer ways to engineer brain cells to function as their own thermostat

Photo by Mike Cohea, Brown University

In most optogenetics work, light is delivered to cells from lasers using fiber optic cables; a new technology being developed called bioluminescent optogenetics as part of research team led by Christopher Moore at Brown University seeks to have cells produce their own light, and then respond to that light, as a way to control their own activity as well as the activities of neighboring cells.

By Richard Asinof

Posted 8/3/15

Why is this story important?

The $1 million award to fund the development of bioluminescent optogenetics technology by a team led by a neuroscience researcher at Brown, shines a bright light on the world-class expertise in collaborative brain research being conducted. The potential opportunity to translate this break-through technology into clinical therapies appears to be huge. Once again, it highlights the importance in supporting the biomedical research sector in Rhode Island as a potential economic driver.

The questions that need to be asked

Where does neuroscience research fit into the new proposed life sciences development planned to be built on the former Route 195 land? Is there an opportunity to create a dedicated state-of-the-art facility for collaborative neuroscience research, enhancing Rhode Island’s reputation as a hub for talent? Is there a way to create a matching state fund to invest in federal research awards at a high enough level – not thousands, but millions of dollars – to create a competitive advantage for Rhode Island?

Under the radar screen

The redesign and engineering of molecules to create their own luminescence and then to respond to light is a much different kind of advanced manufacturing than what is often hyped by economic development forces in Rhode Island. It involves biological engineering of molecules that offer the capability to create a new kind of molecular syntax around calcium channels and signaling. It requires a different way of thinking about cause and effect, and the way that we see ourselves. From an educational standpoint, it would appear to place renewed emphasis on executive functions in the classroom, as promoted by Adele Diamond – and not on standardized testing as norms of excellence.

PROVIDENCE – Imagine if there was a way to genetically modify brain cells on the molecular level so that they were smart enough to emit their own light, through the natural process of bioluminescence, and then to program those brain cells to respond to those lights so that they functioned as a neural thermostat, controlling their own activity or the activity of neighboring cells.

That’s the focus of a new research project now under way, led by Christopher Moore, an associate professor of Neuroscience at Brown University, funded by a new three-year, $1 million grant from the W.M. Keck Foundation.

The new technology, known as bioluminescent optogenetics, or BL-OG, builds upon ongoing work with the technology known as optogenetics, which was first introduced in a practical fashion a decade ago, in 2005.

With optogenetics, neuroscientists were able to use pulses of laser light to control neurons in almost any area of the brain, with precision timing. The technology was a big improvement on the less-than-ideal prior methods of controlling neurons, because it enabled genetically engineered cells to respond, or be suppressed, by the use of different colors of light.

BL-OG removes the need to use an intrusive electrode, with the goal of making the cells capable of emitting light precisely when needed in order to control themselves or their neighbors in an optogenetic fashion.

Moore’s principal collaborator, Ute Hochgeschwender, an associate professor at Central Michigan University, first demonstrated how to make optogenetic cells emit their own light in 2013.

The promising technology could have numerous practical applications if and when it would reach the stage to be approved for use in humans: shutting down overexcited neurons at the onset of an epileptic seizure, focusing on calcium ion channels; normalizing brain activity in Parkinson’s disease; or helping to regulate insulin production in the pancreas by using the technology to serve as a sensor for low blood sugar.

For Moore, the collaboration with Hochgeschwender and the team of his neuroscience colleagues at Brown – including Diane Lipscombe, the interim director of the Brown Institute for Brain Science, along with Julie Kauer and Barry Connors – has opened up a new dynamic in collaborative neuroscience research.

“What’s incredibly cool about Brown is that there is an awesome, wonderful expertise at all levels of the [research] project,” Moore told ConvergenceRI. “Not only the expertise, but a very entrepreneurial spirit to get things done. It makes it really easy to do a project, take what they know, and work together.”

There was recognition, Moore continued, about the value of collaboration, instead of competition, that reflected an appreciation of each other’s talents. “We realized, that instead of competing, we decided to collaborate.” In terms of expertise, Moore sang the praises of his collaborators and their talents.

Here, then, is an interview by ConvergenceRI with Christopher Moore, the team leader of a research project in bioluminescent optogenetics and its promising technology.

ConvergenceRI: How does bioluminescent optogenetics change the technology for brain imaging?MOORE: From the imaging perspective, it may or may not be transformational. The richer implications are in [programming brain cells and how they respond to light].

About 15 years ago, optogenetics emerged, engineering brain cells, making them sensitive to light, and studying how the cells changed in relationship to some action, or perception, such as remembering your phone number.

That was a huge advance. With BL-OG, one of the things you don’t need to do is to put an [invasive optic implant] in the brain. We’ll be producing light with this method, not imaging that light to show what the brain is doing, but controlling what the brain is doing.

ConvergenceRI: How does the new BL-OG technology change the capabilities in understanding brain disorders such as epilepsy?MOORE: In epilepsy, what happens is a group of brain cells, in a spontaneous wave, start to [fire] and spiral into over-activity, which starts to spread, [creating] over-excitability of the brain.

With optogenetics, the opportunity is that when the first brain cells start to shout too loudly, you can shut it down, preventing the seizure, to cut it off at the pass.

What BL-OG will [hopefully] allow us to do is to have the cells sense their own activity, and when they feel that they’re becoming too active, they’re literally able to shine and light and shut off their own [over-reaction]. So that the cell’s membrane, like a thermostat controlling overheating, shuts down that response, so that the cell doesn’t get too hot, turning on the air conditioner.

ConvergenceRI: What are the next steps in terms of engineering that need to be developed to accompany the introduction of bioluminescent optogenetics to more widespread use in neuroscience labs?MOORE: What we’re building are the molecular tools that involve a variety of technologies. All the components work individually; what we are doing is to bring them together – the molecule that produces the light, and then [engineering] the context to allow [the molecule to] receive the light.

That’s a lot of molecular engineering, creating a whole new family of tools for receiving the light.

There is already a lot of innovation on the OG side, with a lot of people working in optogenetics. Every time there is an advance on the optogenetic side, we can leverage that in our molecular engineering.

It’s similar to the way that [technical improvements] in computers have been leveraged to make the next generation of computers [or mobile devices] better.

What we are doing is taking what already exists and making it better: instead of putting a fiber in the head, researchers can put cells in the brain through an injection. The [potential is] to achieve deep brain stimulation, we would be able to get rid of the electrodes.

With BL-OG molecules, you wouldn’t need an electrode implanted in the brain, run by a battery. It’s a potentially huge step forward if everything falls into place.

And, with BL-OG molecules, in terms of the use of drugs, we can potentially get rid of the need [for someone to be] constantly on drugs, to shut the brain down. With brain disorders, [current treatments] involve chronically giving drugs so that the brain that isn’t working properly is shut down.

These are two different advances over the existing methods that may be achieved with the use of BL-OG molecules.

– to get rid of the implanted electrode and to get rid of the chronic use of drugs to shut the brain down.

Instead, with the use of BL-OG molecules, the brain would be able to function and to self-correct – the brain would be in a position to act as its own biological thermostat – to keep it functioning at the right temperature.

ConvergenceRI: How does this work relate to the other members of your team at Brown: on calcium ion channels, on the role of the spinal cord in transmitting pain signals, on the potential treatments for ALS or migraines?MOORE: The work on BL-OG molecules and molecular engineering serves as a bridge to the other ongoing research.

What’s incredibly cool about Brown is that there is an awesome, wonderful expertise at all levels of the [research] project, Not only the expertise, but a very entrepreneurial spirit to get things done. It makes it really easy to do a project, take what they know, and work together. Instead of competing, we decided to collaborate.

Diane [Lipscombe] is one of the top five people in the world in biocalcium biophysics. Her lab’s expertise in designing, engineering and building the molecules is a perfect fit.

Julie Kauer and Barry Connors are experts at testing how the molecules will act at the animal level, and at testing how the systems will work together.

ConvergenceRI: Have you had any direct conversations or contact with Tom Insel, the director of NIMH, regarding your work on BL-OG, given his interest in changing the focus on research on brain disorders away from symptoms and toward a more scientific approach?MOORE: I haven’t talked directly with Tom. What he wants to do is develop a whole new set of tools encompassing research on brain disorders.

For instance, there are 13 effective drug treatments for heart disease that have been developed [based on rational principles], but there are no drugs that have been developed using rational principles on how we want to fix the brain.

We don’t have the mechanisms for translational decisions; we need a much more rational understanding of how things work.

The work on BL-OG molecules is very much on the cutting edge, along with many other new tools that are being developed. It’s an amazing time to be a neuroscientist.

We have a lot of faith that this [work on BL-OG molecules] could be transformative; it’s not just a tool for understanding how the brain works.

ConvergenceRI: Could the use of BL-OG molecules be applied to what’s known as toxic stress, and the way that brain reacts to an overabundance of stress hormones such as cortisol?MOORE: Absolutely; BL-OG is a platform tool.

ConvergenceRI: Does the new BL-OG molecular engineering present opportunities to spin out the technology for commercial and clinical applications beyond the academic lab? Does it create a new kind of brain molecular syntax?MOORE: Of course, this is what our technology and research is focused on, to make optogenetics into a therapy.

It also can do things things that optogenetics cannot do, so it may prove to be clinically highly useful.

There are clearly some therapeutic ideas that can be incorporated. We’re in the very early stages of a high-reward grant.

Depending on how it all turns out, there are many, many different aspects of what we can do with BL-OG. We’re in the very early days.